Novel leukotriene b4 receptor inhibitors and use thereof

Abstract

The present invention relates to N-phenylbenzoxazolo-2-amine and N-phenyloxazolopyridin-2-amine derivatives as novel leukotriene B4 receptor inhibitors, and use thereof.

1 . A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         in Formula 1, 
         X is N or CR 1 , 
         R 1  to R 4  are each independently hydrogen, halogen, nitro, C 1-4  alkyl, or C 1-4  alkoxy, and 
         R 5  to R 9  are each independently hydrogen, amino, nitro, C 1-4  alkoxy, hydroxy-C 1-4  alkylcarbonylamino, C 1-4  alkylcarbonyloxy-C 1-4  alkylcarbonylamino, amino-C 1-4  alkylcarbonylamino, or tert-butoxycarbonylamino-C 1-4  alkylcarbonylamino. 
       
     
     
         2 . The compound or pharmaceutically acceptable salt thereof of  claim 1 ,
 wherein R 1  to R 4  are each independently hydrogen, fluoro, chloro, bromo, nitro, ethyl, tert-butyl, or methoxy.   
     
     
         3 . The compound or pharmaceutically acceptable salt thereof of  claim 1 ,
 wherein R 5  to R 9  are each independently hydrogen, amino, nitro, methoxy, hydroxymethylcarbonylamino, methylcarbonyloxymethylcarbonylamino, tert-butoxycarbonylaminopropylcarbonylamino. tert-butoxycarbonylaminoethylcarbonylamino, or aminopropylcarbonylamino.   
     
     
         4 . The compound or pharmaceutically acceptable salt thereof of  claim 1 ,
 wherein the compound is as follows:   1. 5-fluoro-N-(2-nitrophenyl)benzo[d]oxazol-2-amine,   2. 5-fluoro-N-(3-nitrophenyl)benzo[d]oxazol-2-amine,   3. 5-fluoro-N-(2-methoxy-4-nitrophenyl)benzo[d]oxazol-2-amine,   4. 6-fluoro-N-(3-nitrophenyl)benzo[d]oxazol-2-amine,   5. 6-fluoro-N-(4-nitrophenyl)benzo[d]oxazol-2-amine,   6. 6-fluoro-N-(2-methoxy-4-nitrophenyl)benzo[d]oxazol-2-amine,   7. 5-chloro-N-(2-nitrophenyl)benzo[d]oxazol-2-amine,   8. 5-chloro-N-(4-nitrophenyl)benzo[d]oxazol-2-amine,   9. 6-chloro-N-(3-nitrophenyl)benzo[d]oxazol-2-amine,   10. 6-chloro-N-(2-methoxy-4-nitrophenyl)benzo[d]oxazol-2-amine,   11. 5,7-dichloro-N-(2-nitrophenyl)benzo[d]oxazol-2-amine,   12. 5,7-dichloro-N-(3-nitrophenyl)benzo[d]oxazol-2-amine,   13. 5,7-dichloro-N-(4-nitrophenyl)benzo[d]oxazol-2-amine,   14. 5,7-dichloro-N-(2-methoxy-4-nitrophenyl)benzo[d]oxazol-2-amine,   15. 5-chloro-N-(2-methoxy-4-nitrophenyl)-6-nitrobenzo[d]oxazol-2-amine,   16. 7-chloro-N-(2-methoxy-4-nitrophenyl)-5-nitrobenzo[d]oxazol-2-amine,   17. 5,7-dichloro-6-ethyl-N-(2-methoxy-4-nitrophenyl)benzo[d]oxazol-2-amine,   18. 5-tert-butyl-N-(2-methoxy-4-nitrophenyl)benzo[d]oxazol-2-amine,   19. 5-methoxy-N-(2-methoxy-4-nitrophenyl)benzo[d]oxazol-2-amine,   20. 6-bromo-N-(2-methoxy-4-nitrophenyl)oxazolo[4,5-b]pyridin-2-amine,   21. N1-(5-fluorobenzo[d]oxazol-2-yl)benzene-1,2-diamine,   22. N1-(5-fluorobenzo[d]oxazol-2-yl)benzene-1,3-diamine,   23. N1-(5-fluorobenzo[d]oxazol-2-yl)-2-methoxybenzene-1,4-diamine,   24. N1-(6-fluorobenzo[d]oxazol-2-yl)benzene-1,3-diamine,   25. N1-(6-fluorobenzo[d]oxazol-2-yl)benzene-1,4-diamine,   26. N1-(6-fluorobenzo[d]oxazol-2-yl)-2-methoxybenzene-1,4-diamine,   27. N1-(5-chlorobenzo[d]oxazol-2-yl)benzene-1,2-diamine,   28. N1-(5-chlorobenzo[d]oxazol-2-yl)benzene-1,4-diamine,   29. N1-(6-chlorobenzo[d]oxazol-2-yl)benzene-1,3-diamine,   30. N1-(6-chlorobenzo[d]oxazol-2-yl)-2-methoxybenzene-1,4-diamine,   31. N1-(5,7-dichlorobenzo[d]oxazol-2-yl)benzene-1,2-diamine,   32. N1-(5,7-dichlorobenzo[d]oxazol-2-yl)benzene-1,3-diamine,   33. N1-(5,7-dichlorobenzo[d]oxazol-2-yl)benzene-1,4-diamine,   34. N1-(5,7-dichlorobenzo[d]oxazol-2-yl)-2-methoxybenzene-1,4-diamine,   35. N1-(5-tert-butylbenzo[d]oxazol-2-yl)-2-methoxybenzene-1,4-diamine,   36. 2-methoxy-N1-(5-methoxybenzo[d]oxazol-2-yl)benzene-1,4-diamine,   37. 2-(6-chlorobenzo[d]oxazol-2-ylamino)-5-nitrophenol,   38. 2-(2-(5-fluorobenzo[d]oxazol-2-ylamino)phenylamino)-2-oxoethyl acetate,   39. 2-(3-(5-fluorobenzo[d]oxazol-2-ylamino)phenylamino)-2-oxoethyl acetate,   40. 2-(4-(5-fluorobenzo[d]oxazol-2-ylamino)-3-methoxyphenylamino)-2-oxoethyl acetate,   41. 2-(3-(6-fluorobenzo[d]oxazol-2-ylamino)phenylamino)-2-oxoethyl acetate,   42. 2-(4-(6-fluorobenzo[d]oxazol-2-ylamino)phenylamino)-2-oxoethyl acetate,   43. 2-(4-(6-fluorobenzo[d]oxazol-2-ylamino)-3-methoxyphenylamino)-2-oxoethyl acetate,   44. 2-(2-(5-chlorobenzo[d]oxazol-2-ylamino)phenylamino)-2-oxoethyl acetate,   45. 2-(4-(6-chlorobenzo[d]oxazol-2-ylamino)phenylamino)-2-oxoethyl acetate,   46. 2-(3-(6-chlorobenzo[d]oxazol-2-ylamino)phenylamino)-2-oxoethyl acetate,   47. 2-(2-(5,7-dichlorobenzo[d]oxazol-2-ylamino)phenylamino)-2-oxoethyl acetate,   48. 2-(3-(5,7-dichlorobenzo[d]oxazol-2-ylamino)phenylamino)-2-oxoethyl acetate,   49. 2-(4-(5,7-dichlorobenzo[d]oxazol-2-ylamino)phenylamino)-2-oxoethyl acetate,   50. 2-(4-(5,7-dichlorobenzo[d]oxazol-2-ylamino)-3-methoxyphenylamino)-2-oxoethyl acetate,   51. N-(2-(5-fluorobenzo[d]oxazol-2-ylamino)phenyl)-2-hydroxyacetamide,   52. N-(3-(5-fluorobenzo[d]oxazol-2-ylamino)phenyl)-2-hydroxyacetamide,   53. N-(4-(5-fluorobenzo[d]oxazol-2-ylamino)-3-methoxyphenyl)-2-hydroxyacetamide,   54. N-(3-(6-fluorobenzo[d]oxazol-2-ylamino)phenyl)-2-hydroxyacetamide,   55. N-(4-(6-fluorobenzo[d]oxazol-2-ylamino)phenyl)-2-hydroxyacetamide,   56. N-(4-(6-fluorobenzo[d]oxazol-2-ylamino)-3-methoxyphenyl)-2-hydroxyacetamide,   57. N-(2-(5-chlorobenzo[d]oxazol-2-ylamino)phenyl)-2-hydroxyacetamide,   58. N-(3-(6-chlorobenzo[d]oxazol-2-ylamino)phenyl)-2-hydroxyacetamide,   59. N-(2-(5,7-dichlorobenzo[d]oxazol-2-ylamino)phenyl)-2-hydroxyacetamide,   60. N-(3-(5,7-dichlorobenzo[d]oxazol-2-ylamino)phenyl)-2-hydroxyacetamide,   61. N-(4-(5,7-dichlorobenzo[d]oxazol-2-ylamino)phenyl)-2-hydroxyacetamide,   62. N-(4-(5,7-dichlorobenzo[d]oxazol-2-ylamino)-3-methoxyphenyl)-2-hydroxyacetamide,   63. tert-butyl 3-(4-(5-chlorobenzo[d]oxazol-2-ylamino)phenylamino)-3-oxopropylcarbamate,   64. tert-butyl 4-(4-(5-chlorobenzo[d]oxazol-2-ylamino)phenylamino)-4-oxobutylcarbamate,   65. tert-butyl 4-(4-(5-tert-butylbenzo[d]oxazol-2-ylamino)-3-methoxyphenylamino)-4-oxobutylcarbamate,   66. tert-butyl 4-(3-methoxy-4-(5-methoxybenzo[d]oxazol-2-ylamino)phenylamino)-4-oxobutylcarbamate, or   67. 4-amino-N-(3-methoxy-4-(5-methoxybenzo[d]oxazol-2-ylamino)phenyl)butanamide.   
     
     
         5 . A method of producing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, the method comprising a 1 step of preparing a compound represented by Formula 3 by a cydization reaction of a hydroxyphenyl-thiourea derivative compound represented by Formula 2: 
       
         
           
           
               
               
           
         
         in Formula 1, 
         X is N or CR 1 , 
         R 1  to R 4  are each independently hydrogen, halogen, nitro, C 1-4  alkyl, or C 1-4  alkoxy, and 
         R 5  to R 9  are each independently hydrogen, amino, nitro, C 1-4  alkoxy, hydroxy-C 1-4  alkylcarbonylamino, C 1-4  alkylcarbonyloxy-C 1-4  alkylcarbonylamino, amino-C 1-4  alkylcarbonylamino, or tert-butoxycarbonylamino-C 1-4  alkylcarbonylamino. 
       
     
     
         6 . The method of  claim 5 ,
 wherein the hydroxyphenyl-thiourea derivative compound represented by Formula 2 is prepared by a 1′ step of reacting a 2-aminopyridin-3-ol or 2-aminophenol derivative compound represented by Formula 4 and a nitrophenyl isothiocyanate derivative compound represented by Formula 5:   
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 5 , further comprising: a 2 step of reducing the product obtained from the 1 step to convert a nitro group substituted on a phenyl group into an amine group. 
     
     
         8 . The method of  claim 5 ,
 wherein, when R 6  is alkoxy, the method further comprises a 1-1 step of converting the alkoxy group into a hydroxy group through a dealkylation reaction of the product obtained in the 1 step.   
     
     
         9 . The method of  claim 7 , further comprising: a 3-1 step of reacting the product obtained in the 2 step with 2-halo-2-oxy-C 1-4  alkyl C 1-4  alkanoate to convert the amine group substituted on the phenyl ring into a C 1-4  alkylcarbonyloxy-C 1-4  alkylcarbonylamino group. 
     
     
         10 . The method of  claim 9 , further comprising: a 4-1 step of reacting the product obtained in the 3-1 step under a base to convert the C 1-4  alkylcarbonyloxy-C 1-4  alkylcarbonylamino group substituted on the phenyl ring into a hydroxy-C 1-4  alkylcarbonylamino group. 
     
     
         11 . The method of  claim 7 , further comprising: a 3-2 step of reacting the product obtained from the 2 step with tert-butoxycarbonylamino-C 1-4  alkanoic add to convert the amine group substituted on the phenyl ring into a tert-butoxycarbonylamino-C 1-4  alkylcarbonylamino group. 
     
     
         12 . The method of  claim 11 , further comprising: a 4-2 step of reacting the product obtained from the 3-2 step with an add in an organic solvent to remove a tert-butoxycarbonyl group. 
     
     
         13 . A pharmaceutical composition for preventing or treating diseases related to LTB4 receptor activity, the composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof, as an active ingredient: 
       
         
           
           
               
               
           
         
         in Formula 1 above, 
         X is N or CR 1 , 
         R 1  to R 4  are each independently hydrogen, halogen, nitro, C 1-4  alkyl, or C 1-4  alkoxy, and 
         R 5  to R 9  are each independently hydrogen, amino, nitro, C 1-4  alkoxy, hydroxy-C 1-4  alkylcarbonylamino, C 1-4  alkylcarbonyloxy-C 1-4  alkylcarbonylamino, amino-C 1-4  alkylcarbonylamino, or tert-butoxycarbonylamino-C 1-4  alkylcarbonylamino. 
       
     
     
         14 . The pharmaceutical composition of  claim 13 ,
 wherein the pharmaceutical composition exhibits an effect of inhibiting an increase in cell migration, invasion or both due to activation of BLT2.   
     
     
         15 . The pharmaceutical composition of  claim 13 ,
 wherein diseases related to LTB4 receptor activity are inflammatory diseases, cardiovascular diseases, or cancer diseases.